Patient, heal thyself

By Michael Behar

June 15, 2014 — 3.00am

One morning in May 1998, Kevin Tracey converted a room in his lab at the Feinstein Institute for Medical Research in Manhasset, New York, into a makeshift operating theatre and then prepped his patient - a rat - for surgery.

A neurosurgeon, and also Feinstein Institute's president, Tracey had spent more than a decade searching for a link between nerves and the immune system. His work led him to hypothesise that stimulating the vagus nerve with electricity would alleviate harmful inflammation. ''The vagus nerve is behind the artery where you feel your pulse,'' he told me, pressing his right index finger to his neck.

Illustration: John Spooner.

The vagus nerve and its branches conduct nerve impulses - called action potentials - to every major organ. But communication between nerves and the immune system was considered impossible, according to the scientific consensus in 1998.

Nonetheless, Tracey was certain that an interface existed, and that his rat would prove it. After anaesthetising the animal, Tracey cut an incision in its neck, using a surgical microscope to find his way around his patient's anatomy. With a hand-held nerve stimulator, he delivered several one-second electrical pulses to the rat's exposed vagus nerve. He stitched the cut closed and gave the rat a bacterial toxin known to promote the production of tumour necrosis factor, or TNF, a protein that triggers inflammation in animals, including humans.

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'I think this is the industry that will replace the drug industry' says Dr Kevin Tracey.Credit:New York Times

''We let it sleep for an hour, then took blood tests,'' he said. The bacterial toxin should have triggered rampant inflammation, but instead the production of tumour necrosis factor was blocked by 75 per cent. ''For me, it was a life-changing moment,'' Tracey said. What he had demonstrated was that the nervous system was like a computer terminal through which you could deliver commands to stop a problem, like acute inflammation, before it starts, or repair the body after it gets sick.

Inflammatory afflictions like rheumatoid arthritis and Crohn's disease are currently treated with drugs - painkillers, steroids and what are known as biologics, or genetically engineered proteins. But such medicines, Tracey pointed out, are often expensive, hard to administer, variable in their efficacy and sometimes accompanied by lethal side effects. His work seemed to indicate that electricity delivered to the vagus nerve in just the right intensity and at precise intervals could reproduce a drug's therapeutic reaction. His subsequent research would also show that electricity could do so more effectively than drugs and with minimal health risks.

Tracey's efforts have helped establish what is now the growing field of bioelectronics. He has grand hopes for it. ''I think this is the industry that will replace the drug industry,'' he said. Researchers are creating implants that can communicate directly with the nervous system in order to try to fight everything from cancer to the common cold.

''The list of TNF diseases is long,'' Tracey said. ''So when we created SetPoint'' - the start-up he founded in 2007 with a physician and researcher at Massachusetts General Hospital in Boston - ''we had to figure out what we were going to treat.'' They wanted to start with an illness that could be mitigated by blocking tumour necrosis factor and for which new therapies were desperately needed. Rheumatoid arthritis satisfied both criteria. It afflicts about 1 per cent of the global population, causing chronic inflammation that erodes joints. And there is no cure for it.

In September 2011, SetPoint Medical began the world's first clinical trial to treat rheumatoid arthritis patients with an implantable nerve stimulator based on Tracey's discoveries. According to Ralph Zitnik, SetPoint's chief medical officer, of the 18 patients enrolled in the ongoing trial, two-thirds have improved. And some of them were feeling little or no pain just weeks after receiving the implant; the swelling in their joints had disappeared.

Conceptually, bioelectronics is straightforward: get the nervous system to tell the body to heal itself. But, of course, it's not that simple. The biggest challenge is interpreting the conversation between the body's organs and its nervous system, according to Kris Famm, who runs the newly formed Bioelectronics R&D unit at GlaxoSmithKline, the world's seventh-largest pharmaceutical company. ''No one has really tried to speak the electrical language of the body,'' he says.

Another obstacle is building small implants, some of them as tiny as a cubic millimetre, robust enough to run powerful microprocessors. Should bioelectronics become widely adopted, millions of people could one day be walking around with networked computers hooked up to their nervous systems. And that prospect highlights an issue the industry will eventually have to confront: the possibility of malignant hacking.

Despite the uncertainties, in August last year, GlaxoSmithKline invested $5 million in SetPoint, and Bioelectronics R&D now has partnerships with 26 independent research groups in six countries. Glaxo has also established a $50 million fund to support the science of bioelectronics and is offering a prize of $1 million to the first team to develop an implantable device that can, by recording and responding to an organ's electrical signals, exert influence over its function.

After that first surgery on the rat in 1998, Tracey spent 11 years mapping the neural pathways of tumour necrosis factor inflammation, charting a route from the vagus nerve to the spleen to the bloodstream and eventually to mitochondria inside cells.

By 2009, SetPoint felt ready to test Tracey's work on people with rheumatoid arthritis, and Zitnik was approached about joining the company. ''It was nuts,'' Zitnik said. ''Sticking something on the vagus nerve to take away RA? People would think it's witchcraft.''

Zitnik's background was in pharmaceuticals. But the more he talked with Tracey and pored over the research, the more he said to himself: ''There is good science behind this. I thought, 'This could work'.''

Zitnik's first task at SetPoint was to recruit a lead scientist to set up a clinical trial. Many scientists in the United States and Europe were hesitant to do it, he says, but eventually he hired Paul-Peter Tak, a well-regarded immunologist and rheumatologist based at the Academic Medical Centre, the University of Amsterdam's teaching hospital. (Tak is now Glaxo's global head of immuno-inflammation research.)

Tak in turn hired Frieda Koopman, who was working on her PhD in rheumatology at AMC, to find potential patients in the Netherlands and elsewhere in Europe.

The day after an article about the planned trial appeared in a Dutch newspaper in 2011, Koopman's office got more than 1000 calls from rheumatoid arthritis patients begging to participate. Koopman's team selected several subjects based on what medications they had tried and the severity of the pain and swelling in their joints. Over the next two years, her team continued to enroll new patients.

The subjects in the trial each underwent a 45-minute operation. A neurosurgeon fixed an inch-long device shaped like a corkscrew to the vagus nerve on the left side of the neck, and then embedded just below the collarbone a silver-dollar-size ''pulse generator'' that contained a battery and microprocessor programmed to discharge mild shocks from two electrodes. A thin wire made of a platinum alloy connected the two components beneath the skin.

Once the implant was turned on, its preprogrammed charge - about 1 milliamp - zapped the vagus nerve in 60-second bursts, up to four times a day. After a week or two, arthritic pain began to subside. Swollen joints shrank, and blood tests that checked for inflammatory markers usually showed striking declines.

When I joined Famm in Philadelphia in February, he referred to his role as Glaxo's bioelectronics chief as ''like being a missionary''. Famm, who lives in London, was in the US to attend meetings with bioelectronics researchers.

His challenge is coaxing those from disparate disciplines to embrace a singular vision. Whereas drug discovery primarily involves like-minded thinkers (molecular biologists, chemists, geneticists), bioelectronics calls for alliances between experts in fields that in many cases have little to do with medicine - nanotech, optics, electrical engineering, computer programming. Famm is focused on getting what he called a ''transdisciplinary'' group of scientists to agree on how to solve two key technical challenges.

The first is shrinking the hardware. It must be small enough to attach to virtually any nerve yet still have enough battery power and circuitry to run algorithms that generate the patterns of electrical impulses needed to treat various diseases.

At the Charles Stark Draper Laboratory in Cambridge, Massachusetts, we met with a team working on miniaturisation. Draper is best known for internal navigation systems that guide things such as ballistic missiles and spaceships. Bryan McLaughlin, who directs bioelectronics development at Draper, showed me the latest prototype mock-up - a dime-size implant. It's small, he said, but not nearly small enough. McLaughlin wants to get its electrodes, microprocessor, battery and a wireless transmitter into a device no larger than a jelly bean. ''It's also important to make it closed-loop, with the ability to read and write to the nervous system.'' The goal is to end up with something that can continuously monitor a patient and then dispense bioelectronic therapy as needed.

The second challenge is devising a method to make sense of signals emanating simultaneously from hundreds of thousands of neurons. Accurate recording and analysis are essential to bioelectronics in order for researchers to identify the discrepancies between baseline neural signals in healthy individuals and those produced by someone with a particular disease.

The conventional approach to recording neural signals is to use tiny probes with electrodes inside called patch clamps. A prostate cancer researcher, for example, could attach patch clamps to a nerve linked to the prostate in a healthy mouse and record the activity. The same thing would be done with a mouse whose prostate had been genetically engineered to produce malignant tumours. Comparing the output from both might allow the researcher to determine how the neural signals differ in cancerous mice. From such data, a corrective signal could be programmed into a bioelectronic device to treat the cancer.

But there are drawbacks to using patch clamps. They can sample only one cell's activity at a time, and therefore fail to gather enough data to see the big picture. As Adam Cohen, who teaches chemistry and physics at Harvard, puts it: ''It's like trying to watch an opera through a straw.''

Surmounting these sorts of technical hurdles ''might take 10 years'', Famm figures. That seems somewhat optimistic if you consider Glaxo's investment so far in bioelectronics. Melinda Stubbee, the company's director of communications, says it has spent roughly $60 million in the area, a pittance compared with its $6.5 billion in total research and development expenditure in 2013.

At one point, Famm referred to detractors who say bioelectronics is ''too risky, will take too long and is maybe even a bit bonkers''. In trying to find some of them, I contacted a number of financial analysts who track Glaxo and the pharmaceutical industry. One, Mark Clark, at Deutsche Bank, said in an email: ''I know next to nothing about this early-stage technology! I am prepared to bet you will not find a single Glaxo analyst that knows anything about this!''

In short, the fledgling bioelectronics industry is nowhere near mature enough for analysts to make meaningful estimates about its revenue potential. But people like Clark will certainly begin paying closer attention if bioelectronics starts to capture even a sliver of the lucrative pharmaceutical market.

Yet if large numbers of patients someday choose bioelectronics over drugs, another issue awaits resolution: security. Bioelectronics devices will feature wireless connectivity so they can be fine-tuned and upgraded, ''just like the software on your iPhone'', Famm says. And wireless means hackable, a fact that worries two experts on medical-device security: Niraj Jha, a professor of electrical engineering at Princeton University, and Anand Raghunathan, who runs the Integrated Systems Laboratory at Purdue University.

According to Jha and Raghunathan, there are no known cases of malicious attacks on medical devices. Nevertheless, Raghunathan says, ''society should be warned about these possibilities''.

Last August, the US Food and Drug Administration offered guidelines to medical-device manufacturers, recommending ''wireless protection'' to reduce ''risks to patients from a security breach''. Whether bioelectronics developers do anything to thwart hacking (the FDA guidelines are not mandatory) may ultimately depend on whether Jha and Raghunathan's fears are realised.

McLaughlin doesn't dismiss these concerns but notes there is no ''incentive for device companies to do anything about security''. He adds: ''Nobody has been sued. No patient has died. But the first event that occurs with one of these devices - companies will jump on it and create secure platforms.''

SetPoint's chief technology officer is Mike Faltys, a medical engineer who was integral to designing the modern cochlear implant. Faltys worked for six years out of his garage, first re-engineering an existing electrical stimulator, used to stop seizures, that became the device implanted in patients in SetPoint's trial, and more recently finished a significantly more advanced implantable unit that he calls ''the microregulator''.

Housed in a pod shaped like a hot-dog bun and the size of a multivitamin, the microregulator is entirely self-contained - onboard battery, microprocessor and electrodes are integrated into a single unit.

It can be wirelessly recharged, and adjusted with an iPad app. The surgery to clamp it on to the vagus nerve will take about 20 minutes, and once in place, it will provide pain relief to a rheumatoid-arthritis patient for a decade or more before it needs servicing.

On one occasion during my travels with Famm, I got to hold SetPoint's newfangled microregulator. For now, it's only capable of transmitting very crude signals to communicate with the nervous system. Even so, the microregulator felt powerful and promising in my palm.

''A patient gets a device like this implanted once for one disease, and they're done,'' Tracey says. ''No prescriptions, no medicines, no injections. That's the future. That's what gets me out of bed in the morning.''

The New York Times Magazine

Michael Behar writes about science and the environment. His work has appeared in The Best American Travel Writing and The Best American Science and Nature Writing. This article was adapted from one that originally appeared in The New York Times Magazine.